PT88220B - PROCESS OF PREPARATION OF AN IMPLANT WITH CONTRACEPTIVE ACTION - Google Patents

Abstract

The invention relates to an implant of polymeric material which can release a contraceptive agent for a relatively long time when fitted subcutaneously or locally.

Description

DESCRIPTION

GIVES

INVENTION PATENT

No. 88 220

APPLICANT: AKZO N.V., Dutch, industrial, with headquarters at Velperweg 76, 6824 BM Arnhem, Netherlands.

EPIGRAPH: PROCESS OF PREPARING AN IMPLANT WITH

CONTRACEPTIVE ACTION.

INVENTORS: Hendrik De Nijs.

Claim of the right of priority under Article 4 of the Paris Convention of 20 March 1883.

Netherlands on August 8, 1987 under No. ² . 87.01868.

INP1. MOD. 113 B F 1W32

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PATENT NO. ΘΘ 220

Process of preparing an implant with contraceptive action so that

AKZO N.U., intends to obtain privilege of invention in Portugal.

SUMMARY The present invention relates to the process for preparing an implant with contraceptive action intended for subcutaneous or local administration, characterized by the co-axial extrusion of:

a) ethylene / vinyl acetate copolymer core material (hereinafter referred to as USA), having a molecular weight such that the melt index is greater than 10 grams / 10 minutes, and a vinyl acetate content of 20% by weight or more, core material containing 3-keto-desogestrel, levonorgestrel or gestodene as an active contraceptive substance in an amount that is sufficient for the sustained long-term release of about at least 15-30 µg of active substance per day, and

b) a membrane material which covers the core material and which also consists of USA material, but with a molecular weight such that the melt index is less than 10 grams / 10 minutes, and a vinyl acetate content of less than 20 % by weight; resulting in a virtual or completely cylindrical implant, with a maximum external diameter of about 2 mm, a length of less than about 5 cm and a membrane layer thickness of 50-2 50 _M m.

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-2 DESCRIPTIVE MEMORY

The invention relates to the process of preparing an implant of polymeric material that can release a contraceptive agent over a relatively long period of time, when placed subcutaneously or locally. More specifically, the invention relates to an implant of such small dimensions that it can be placed subcutaneously with a common hypodermic needle.

There is a great need for the development of new, long-acting contraceptives that require minimal medical guidance. This is particularly true for those areas of the world where medical infrastructure is poor, and where family planning can only be organized to an insufficient degree.

An implant of this type, which can release a contraceptive agent in virtually constant amounts over a period of at least 2 years, more preferably for about 4 to 5 years, is new progress that can certainly provide what is needed. The biggest problem, however, is often the large amount of contraceptive agent with which the implant material has to be loaded to ensure release for about 4 years, which leads to very bulky implants that can only be surgically placed or to several smaller implants that have to be placed simultaneously.

Currently, the need for subcutaneous placement of a plurality of (smaller) implants is also unattractive.

In theory, it is suitable for the development of an implant, any polymeric material, as long as it is biologically compatible, and also any material with a progestational action. In this context, reference should be made, for example, to U.S. Patent NS. 3 279 996 (Long et al.) In which an implant is described which contains an active substance wrapped in a polysiloxane membrane and Dutch Patent 167 850 (Zaffaroni) in which an implant is described in which the active substance is contained in a polymer, and this polymer loaded with the active substance is surrounded by a polymer membrane that controls

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-3la completely the release speed. However, if a limit is determined on the dimensions of the implant, if a certain rigidity of the implant is required to facilitate its introduction and if, in addition, a duration of release of the contraceptive substance is desired for a minimum of 2 years, and preferably from 4 to 5 years, then all theoretical solutions available to fail.

The implant of the invention can be considered one of the release systems known per se, which consists of a core of active material surrounded by a membrane regulating the rate of release. The choice of polymers to be used, the choice of contraceptive substances, and the dimensions of the implant are, however, combined in such a way that only a delivery system is obtained that completely complies with all the requirements stipulated above.

The implant of the invention is cylindrical or virtually cylindrical, with a maximum cross-section of about 2 mm, but preferably between 1.5 and 2 mm, and has a variable length. □ implant length, however, will not exceed 5 cm for practical reasons. The length is preferably between 1 and 4 cm. These implant dimensions of the invention are so small that subcutaneous placement can be performed with a standard hypodermic needle.

The implant of the invention is characterized by:

a) core material in ethylene acetate / vinyl acetate copolymer (hereinafter referred to as AEV), having a molecular weight such that the melting index is greater than 10 grams / 10 minutes, and a vinyl acetate content 20 / er. weight or more, the core material functioning as a matrix for 3-keto-gestrel, levonorgestrel or gestodene, as active contraceptive substances, in an amount that is sufficient for the constant, long-lasting release of about 15-30 ^ _tx g of substance) a membrane having a layer thickness of 50-250 which surrounds the core material and which is also composed of AEV material, but with a molecular weight <such that the melt index is less than 10 grams / 10 minutes, and with a lower acetate content * <».

· $. *

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-4 than 20% by weight; this implant is completely or virtually cylindrical, with a maximum external diameter of about 2 mm and a length less than about 5 cm.

The contraceptive active substance, which can be used in the context of the present invention, is a highly active progestogen, particularly 3-keto-desogestrel, levonorgestrel or gesture, otherwise. These contraceptive substances are highly active substances that already have an effective progestational action with a daily dosage of around 15-30yxg.

This core material can be loaded with up to about 75% by weight of active substance without seriously affecting the usefulness of the AEV core material. However, a degree of loading of about 50-60% by weight is preferred.

The core material used in the present invention is a powder. AEV polymer with a melt index greater than 10 grams / 10 minutes and preferably between 25 and 30 g / 10 minutes. The vinyl acetate content of the core material is greater than 20% by weight and preferably greater than 25% by weight.

They are very suitable AEV polymers, which can be used (R) as core material, for example, Euatane with the designations 28-150, 28-399 and 28-400, supplied by ICI and 28,420 and (R) in particular 28.25 and 33.25 supplied by Atochem, and Elvax 'under the designations 310, 250, 230, 220 and 210, supplied by Du Pont de Nemours.

The membrane polymer is also an AEV polymer, which however has a higher molecular weight than the core material. The melt index of this membrane material is less than 10 g / 10 min, preferably less than or equal to 8 g / 10 min; the vinyl acetate content is less than 20% by weight.

Suitable AEV polymers that can be used as fp Ί a membrane are, for example, Evatane ' ^{1 1} with the designations 501/502 (melt index 2; content of vinyl acetate 7.5%), 554/555 ( 4; 12.5%), 540 (10; 18%) and particularly 571 (8; 15%), Elvax ^^ with the designations 450, 460, 470, 550, 560, 650, 660, 670, 750,

760 and 770 and Evatane ^^ 1080 VN 5 and in particular 1040 VN 4 forne67 996

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-5 acids by Atochem.

The release characteristics of the contraceptive substance. Water (across the membrane) is largely determined by the vinyl acetate content of the AEU membrane.

The implant of the invention is obtained by means of the so-called coaxial extrusion process, a method in which the two AEV polymers are extruded coaxially in a predetermined layer thickness with the help of a coaxial extrusion head.

This co-axial extrusion process means that both polymers are transported in the molten state through the co-axial extrusion head, containing the material of the molten core at the same time, the active substance.

For this co-axial extrusion process, a contact layer is produced at the interface of the two polymers, the layer being probably completely or partially responsible for the excellent properties of the co-extrudate in drug release, but in any case, avoid. that the two layers of polymers work loose from each other after a certain period of time, due to the disappearance of the polymer's active substance from the core, a shutdown that would fundamentally affect the release pattern.

The coaxial extrusion process is a technique known per se so it will not be further investigated within the scope of this description.

Through the coaxial extrusion process, a thick coaxial filament is obtained, with a maximum external diameter of about 2 mm, and preferably between 1.5 and 2.0 mm. □ the filament is then cut into pieces with a maximum length of about 5 cm, using conventional techniques.

Although, of course, it is not necessary, the cyclic ends of the implant can - if desired - be additionally protected with an inert polymer, for example polyethylene, polypropylene or the AEV polymer used for the membrane, or even, for example, by an adhesive silicone (medical grade). This protective layer is obtained, for example, by dipping the surface in a solution or melt of the particular polymer. If necessary,

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-6 end can be burnt lightly or tightened closely.

Another embodiment of the process implant has, in addition to the assembly described above, a thin layer of polysiloxane surrounding the entire external surface of the implant described above. This polysiloxane is chosen so that the release pattern is not influenced to an appreciable extent; the formation of a second release rate regulation layer is therefore not the objective sought by the latter layer.

The layer in question can therefore be extremely thin, even on the order of about 20-50 yxm; a somewhat thicker layer is, however, also permitted.

This orthographic layer can be obtained by immersing or immersing the implant in a thin polysiloxane tubing.

The implant of the invention must, in each case, contain a quantity, or quantity of active substance sufficient that / when used for human application, it can guarantee a virtually constant release of active substance for a minimum of 1 year, which generally means that the core material should be loaded with 5 to 15 mg of 3-keto desogestrel, 1 evonorgestrel or gestodene. An additional amount of about 5 to 15 mg of active substance is required for each additional year that the implant is to release, so that 25-75 mg of active substance is needed for a release duration of 5 years.

The implant of the invention is preferably to be used as a subcutaneous implant, but it can also be applied locally, for example, in the uterine or cervical region.

Example 1

The active substance, 3-keto-desogestrel, and the AEV core material (melting index 400 q / 10 min; vinyl acetate content 28 / wt) -Ε v atane '' 28-400 - were mixed in a 1: 1 ratio (based on weight) in a heatable mill at 80 ° C. The polymer sheets loaded with 3-keto-desogestrel were reduced in size and then processed into pellets using an extruder and a so-called chipper.

Pellets loaded with 3-keto desogestrel, intended for —Cf

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-7 to the core, and the AEV beads, destined for the membrane (melting index 8 q / 10 minutes; vinyl acetate content, 15% by weight; Evatane ^ 57l), were transferred to two different funnels, from the extrusion apparatus coaxial. The coaxial filament was extruded at a temperature of about 110 ° C. A coaxial filament with an outer diameter of 1.9 mm and a film thickness of 150 µ ω was obtained by the correct choice and correct adjustment of the geometry of the spinning apparatus, the feed speeds of the core material and of the film to the spinner and the speed of winding of the fiber. The extruded coaxial filament was cooled in a water bath, and then wound in coils with a stretch index of 0.25 N. The extrusion speed of the filament was 2.3 meters per second. Typical preparation conditions:

Extruder (drum) Extruder (core) T age (° C) 100 80 Pressure (Pan) 60 χ 10 ⁵ 5 χ 10 ⁵ - -> 173 χ 10 ⁵ 46 χ 10 ⁵ Spinning apparatus 100 0 filament extruded coaxial was, then, cut in

required length. The filament pieces were wrapped in polysiloxane, if desired, using polysiloxane tubing (internal / external diameter dimensions of 1.57 / 2.41 mm) to be swollen in cyclohexane and then filled with the required length coaxial filament, and thin dry under vacuum. The two ends of the implant obtained were sealed with silicone adhesive (low quality). The external diameter of the implant equipped with the polysiloxane layer was 2.5 mm; the external diameter of the implant without the polysiloxane layer was 1.9 mm.

The in vitro release of 3-keto desogestrel from the implant was tested in 250 ml of demineralized water at 3780. This medium was enclosed in a 300 ml conical flask which was shaken at 150 cycles / minute at a range of 2 , 5 cm.

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8Results

Table 1

In vitro release of te 3 cm ccm and without a

3-cetc-desoce3trei an implanted outer layer of polysiloxane.

Release y.cm,

Day

7 9 without polysiloxane layer

10.0

10.7

11.3

10.3

10.3 10.0 10.0

10.3 with polysiloxane layer

6.7

9.7 10.0

9.7

9.3

9.7

9.7

9.7

Here, the outer polysiloxane layer has virtually no influence on the release pattern

Table 2

Day

100

200

300

376

In vitro release of 3-keto-desogestrel from an implant (3 cm) prepared according to this method and provided with a layer of polysiloxane. The implant was sterilized by heating (20 min, 120 ° C).

Release (^ g / day.cm)

57.0 *

14.7

10.3

11.3

10.3 10.0 10.0

9.0

9.3

8.7

8.3

8.3

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-9400

471

500

550

600

650

700

750

800

7.7

7.7 3.0

7.7 8.0 7.0

6.3 6.0

6.5 reinforcement of 3-keto-desogestrel due to heat sterilization. Table 3

Day

In vivo release ”

Average plasma concentrations (3 dogs) of 3-keto-desogestrel after subcutaneous introduction of an implant prepare the second method (see implant in Table 2).

Plasma concentration (pmol / ml), 11 ^K 0.81 0.62 0.66 0.46 0.53 0.49 0.56 0.56 0.56 0.54 0.59 0.60 0.59 0 , 59 0.63 reinforcement of 3-keto-desogestrel due to heat sterilization.

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-10Example 2 (R)

The active substance 3-keto-desogestrel and Evatana ^k 28-400 were mixed in a 1: 1 weight ratio in a 10 mm extruder at 130 ° C.

The extrudate obtained was granulated with the acid of a pelletizer, after which the pellets were heated in vacuo to 1,352 ° C, for one hour.

In the same way as described in Example 1, a filament c_o

-axial was extruded using the pellets loaded with 3-keto desogestrel, referred to above, as core material and the unloaded Evatane 571 (R) pellets as membrane material. The thickness of the coaxial fiber membrane was 135 µm, and the external diameter of the implant was 1.65 mm. The dimensions of the polysiloxane tubing were: 1.47 (inner diameter) x 1.95 mm (outer diameter). The ends of the 4 cm long implant were sealed with low-quality silicone adhesive. The outside diameter of an implant equipped with a layer of polysiloxane was 2.05 mm.

Typical preparation conditions for the relevant coaxial filament.

Extruder (drum) Extruder (core) Spinning Apparatus

Te mp ra ra ra (QC) -> 100 70 -> 85 100

Table 4

P ression (Pa) χ 10 ⁵ -> 160 χ 10 ⁵ 60 x 10 ⁵ -> 70 χ 10 ⁵

In vitro release of 3-keto desogestrel from this 4 cm long implant. The implant was sterilized by gamma rays (25 kGy).

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-11Day

100 150 200 250 300 350 400 4 5 0 500 550

Release yAg / dia.cm)

10.0 *

7, a

7.3

7.5 3.0

7.8

7.3

7.3

7.3 6.0

6.5 6.0

5.5

5.8

5.3 5.0

4.6

4.3 4.0 reinforcement of 3-keto-desogsstrel is minimal if gamma ray sterilization is used in heat sterilization.

Example 3

Analogously to Example 2, the coaxial filament was spun, but in this case with a membrane thickness of 90yum. The external diameter of the implant, in this case, was also about 1.65 mm. The polysiloxane tubing (1.47 x 1.95 mm) was used again for the polysiloxane jacket and the ends were sealed with medical grade silicone adhesive. The external diameter of the implant provided with a polysiloxane layer was 2.05 mm.

Typical preparation conditions for coaxial filament:

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Pressure (Pa)

Extruder (drum) Extruder (core) Spinning apparatus

-12T temperature (SC) -> IDO 60 -> 100 125

160 x 10 150 x 10 ^!

150 x 110 x

10 '

10 'implant length was 3 cm.

Table 5

In vitro release of 3-keto desogestrel from this unsterile implant

ι. cm)

Day

Release Ç ^ g / day,

13.7

9.7

9.7

10.7

10.7

9.3

9.0

8.7.

9.7

9.3

9.0

9.3

100 8.3

110 9.0

Example 4 coaxial filament was obtained according to the method described in Example 2.

(r) filament consists of Euatane (R) core and Euatane 1040 VN 4 as the membrane material.

Additional data:

des

28.25 as material of the membrane thickness: 75 µm;

core material loaded with 60% (weight) 3-keto desogestrel;

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-13Day

I

100

110

120

130

140

150

160 pius 4 external diameter of the implant: 1.7 mm; implant length: 3.0 cm;

outer diameter with polysiloxane housing: 2.05 mm; implant ends sealed with silicone adhesive.

Table 6

In vitro release from the non-sterile implant Release (^ g / day.cm)

24.7 22.0

13.7

12.3

12.3 11.0

11.3

11.3 11.0 11.0

10.7

10.3

10.3

3.3 10.0

8.7

8.3

9.3

Example 5

Same procedure and material, as described in the ExemSpecifications:

(R) core material: Evatane ^k '28.25; membrane: Evatane ^^ 1040 VN 4;

membrane thickness: 60 µm;

core loaded with 60% (weight) of 3-keto desogestrel; external diameter: 2.0 mm; length: 4.0 cm;

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-14without polysiloxane wrapping implant ends not salads.

Table 7

In vitro release

Day

20 30 4 0 50 60 70 SC 90

100

110

120

Release (^ pg / day.cm)

43.9

27.8

24.9

21.3 21.1

18.9

19.1

17.4

15.4

16.1

13.5 16.8

16.5

16.3

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Claims (4)

IVINDICATIONS 1 - Process for the preparation of an implant with contraceptive action intended for subcutaneous or local administration, characterized by the co-axial extrusion of: a) material of the ethylene / vinyl acetate copolymer core (hereinafter referred to as ΕVA), having a molecular weight such that the melting index is greater than 10 grams / 10 minutes, and a vinyl acetate content of 20.0 in weight or more, core material containing 5-keto-desogestrel, levonorgestrel or gestodene as active substance in an amount that is sufficient for the long-term constant release of at least about 15-30 µg of active substance per day, and b) a membrane material which covers the core material and which also consists of E7A material, but with a molecular weight such that the melt index is less than 10 grams / 10 minutes, and a vinyl acetate content of less than 20 , 0 by weight; resulting in a virtual implant cu completely cylindrical, with a maximum external diameter d; ca mm a cimentoriment less than about 5 cm and a membrane layer thickness of 50-25 ° C. Process according to claim 1, characterized in that a Ε VA polymer is used as the core material with a melt index of between 25 s and 30 grams / 10 minutes, and a vinyl acetate content of more than 25, in weight. Process according to claim 1, characterized in that the EVA material is used as the membrane material with a melt index less than or equal to 8 grams / 10 minutes and a vinyl acetate content of less than 20% by weight. 4 - Process according to claim 1, characterized in that 3-keto-desogestrel Lisboa is used as contraceptive substance,